Dermal disorders in companion animals are a common problem. These disorders can be caused by various issues including atopic dermatitis, irritant contact dermatitis, allergic contact dermatitis, yeast infections, folliculitis, impetigo, seborrhea, ringworm, alopecia, mange, flea, tick, dry skin, acral lick dermatitis, hot spots, immune disorders, or skin tumors.
One of the more important dermal disorders is atopic dermatitis. Atopic dermatitis is a form of allergy that is a common problem in 10-15% of all dogs and a similar number in cats. The term atopic in this sense means the animal has a predisposition toward developing certain allergic hypersensitivity reactions associated with an excessive IgE reaction in the skin. Dogs, for example, almost always show allergic reactions through their skin regardless of its source. This means that not only atopy shows as itchy skin, but so do food allergy and insect bite allergy. Some specific signs of canine atopic dermatitis (CAD) include excessive chewing, licking and scratching at the face, paws, abdomen, armpits and genital area. The biting and scratching can cause much hair loss, skin lesions and inflammation.
While allergies can come from food, bacteria, or fleas, atopic dermatitis is typically acquired by inhalation of allergens such as tree pollen, grass pollen, human dander, dust mites, molds, house dust, feathers and other airborne particles. Any airborne particle can potentially become an allergen (irritant) to cause atopic dermatitis. These allergens can result in specific IgE antibodies against them to ultimately cause atopic dermatitis. An atopy/inhalant dog allergy is usually associated with certain areas of the dog's body. This can include areas around the eyes and mouth, the armpits, the abdomen, around the anus, and the legs.
Atopic dermatitis is mediated by the immune system through IgE antibodies, mast cells and histamine release. As a very simplified physiological explanation of atopic dermatitis, allergens, such as pollens, are inhaled or they simply cross the skin where they encounter and bind to IgE molecules present on mast cells of the immune system. The mast cells become activated to release histamine or other mediators. These chemical mediators propagate an excessive inflammatory response characterized by blood vessel dilation, production of pro-inflammatory molecules, cytokine release, and recruitment of leukocytes. This causes redness and swelling of the skin to occur and the subsequent itching response by the dog.
During this sequence of events in atopic dermatitis, arachidonic acid in cell membranes is metabolized to produce the previously mentioned pro-inflammatory molecules that include certain prostaglandins and leukotrienes. The metabolic pathways to produce prostaglandins and leukotrienes are mediated by certain enzymes, including cyclooxygenase I, cyclooxygenase II and 5-lipoxygenase. These enzymes have been favorite targets to inhibit by the drug approach in attempts to alleviate the symptoms of atopic dermatitis. Atopic dermatitis appears to involve multiple 5-Lipoxygenase pathway eicosanoids and receptor subtypes, suggesting that inhibition of the pathway at the level of 5-Lipoxygenase may be necessary for maximal efficacy to reduce atopic dermatitis (Rubin).
While maintaining normal skin health in dogs with CAD has been the goal, CAD is hard to treat under most circumstances as many different factors could be contributing to the problem. Unfortunately, no cure has been found to resolve atopy, but several treatment options are available to control the symptoms. The best solution theoretically is to avoid the allergen. But this may prove to be too difficult a task. A veterinarian might try a sequence of treatment options with the dog, starting with efficient flea control and making sure there are no complicating diseases are occurring in the animal. Then, a trial of various antihistamine drugs in conjunction with the use of fatty acids might take place. If that does not work for the dog, then trials with corticosteroid drugs might occur. If that does not work then hyposensitizing vaccines can be tried to reduce the symptoms of CAD.
There are pros and cons to these traditional drug approaches. There are no guarantees of success with the usual drug orientated treatments. In addition, the usual treatments are costly and can take many months to work. Further, steroid drugs can have undesirable side effects. With antihistamines, it may have to be tried with several different types. Dog allergy vaccinations shots may take a long time to take effect. Additional antibiotics for ear infections or other secondary infections may also have to be used.
An alternative method is needed to help reduce atopic dermatitis that is not drug oriented and does not have the issues associated with the traditional approaches. While no one single approach seems to be fully effective, a combination of elements is required in an alternative approach. However, it is not obvious what the best combination of elements is required or what the best delivery system is for these elements.
Currently, numerous fatty acid supplements are marketed to veterinarians as safe, effective alternatives to systemic glucocorticoids in the treatment of canine pruritic skin disease. The majority of these supplements contain a mixture of polyunsaturated fatty acids (PUFA) including omega-3 PUFA, such as eicosapentaenoic acid (EPA) and docosahexanenoic acid (DHA). In theory, the addition of EPA and DHA to the diet causes the displacement of arachidonic acid (AA) with EPA or DHA in cell membranes and a subsequent decrease in production of pro-inflammatory eicosanoids from AA for the less inflammatory eicosanoids of EPA. This leads to a modification of both platelet and neutrophil responses which in turn decreases clinical evidence of inflammation. Less inflammation means less atopic dermatitis.
Omega-6 fatty acids have also been used in treating atopic dermatitis. The stratum corneum of atopic dogs was characterized by a significant decrease in the lipid content when compared to the healthy controls. Following oral supplementation with a mixture of essential omega-6 and omega-3 fatty acids, the overall lipid content of the stratum corneum markedly increased (Popa). Evening primrose containing omega-6 fatty acid has been shown to help CAD and can be added to the formulation (Scarf).
A dose of 40-50 mg of EPA/kg/day (equivalent to 1 ml of cold water marine fish oil per 4 kg of body weight) has been shown in multiple studies to be somewhat effective in reducing pruritus in CAD (Loga, Mueller). However, only about 15-20% of atopic dogs can be controlled with fatty acid therapy alone while a significant proportion of others have a reduction in pruritus that permits reduction of cortisone doses. However, it can help. Even dogs not obviously responding to fatty acid supplement alone can be treated with lower doses of prednisolone. Withdrawal of polyunsaturated fatty acid therapy and substitution with a control diet in dogs responding to omega-3-omega-6 therapy results in deterioration. As such, supplementing with EPA/DHA and fish oil is a good start, but it is only partially the answer.
The lipid matrix in the stratum corneum is important to the barrier function of mammalian skin. Ceramides are main components of intercellular lipids in the stratum corneum and play an essential role in skin barrier function. Studies suggest that decreased amounts of ceramides in the skin of dogs with CAD may be involved in the impaired barrier function of their skin (Reiter). Ceramide deficiency leads to increased permeability and increased allergen penetration and sensitization. It is currently unknown whether this dysfunction is primary and genetically inherited or secondary to inflammation. However, it is accepted that skin barrier deficiency plays an important role in either starting or minimally exacerbating CAD.
Thus, the therapeutic approach is changing from focusing on the control of the inflammation to a combined approach that includes therapies aimed at skin barrier repair. A study of 4 weeks of topical administration of an emulsion containing ceramides, free fatty acids, and cholesterol (skin lipid complex) led to significantly increased values for ceramides (Ji Young). In another study (Marsella), a commercial topical application of a ceramide-based treatment (ALLERDERM SPOT ON, Virbac, Inc., Fort Worth, Tex.) helped to decrease clinical signs of CAD in dogs that had failed to respond to other therapies. The beneficial effect was most evident after several weeks of therapy with a statistically significant reduction of CADESI and specific reduction of erythema from the baseline after 6 weeks. CADESI is a Canine Atopic Dermatitis Extent and Severity Index, which is a means of objectively assessing the severity of clinical signs in CAD. The authors concluded that this topical treatment modality is best used as adjunctive therapy. Another unpublished study evaluating the same formulation in a blinded and controlled fashion confirmed the beneficial effect in CAD.
All of these studies with ceramides involved the use of topical applications. Topical applications are inconvenient to use and are messy. It has not been obvious to use oral ceramides to treat animals for atopic dermatitis since only small amounts of ceramides have been used in topicals. Further, it is not expected that the amount of oral ceramides used in topical applications could make their way all the way through the gastrointestinal tract and eventually make their way to the skin. Absorbing ceramides from the outer surface of the skin has always appeared to be a far more direct route.
However, some studies have unexpectedly demonstrated that some ceramide orally administered can gradually distribute in the dermis after gastrointestinal absorption, followed by transfer from the dermis to the epidermis (Osomu). Based on these results, it was concluded that the administered ceramide or its metabolite(s) are likely to be involved in the improvement effect on barrier function after arriving in the skin. Other studies have shown that oral intake of glucosylceramide reduced transepidermal water loss in mice and human subjects. (Uchiyama).
Studies have shown that the sphingoids c18:2 and t18:1 activated genes related to de novo ceramide synthesis and increased ceramide production, whereas glucosylceramide and 4-sphingenine could not. These results suggest that the effect of dietary glucosylceramides on the skin is mediated by c18:2 and t18:1 (Shirakura). Nine species of sphingoids are commonly found in plants and many sources of glucosylceramide other than konjac tuber exist, e.g., rice bran, corn, apple, and sugar beet pulp. These glucosylceramides also contain c18:2 and t18:1, but these sphingoids are not as abundant as in konjac, suggesting that konjac is the most effective source of material for improving skin ceramide production. Because the amount of glucosylceramide ingestion is so limited, it is believed that improvement of the skin is not due to the direct localization of glucosylceramide to the skin. At least part of the mechanism involves a triggering of the ceramide synthesis pathway by c18:2 and t18:1. One disclosure, US Patent Publication 2005/0196461 to Udell, is directed to an orally administered formulation containing ceramides in an ingestible soft gelatin capsule for treating conditions such as dry skin and wrinkles in humans. However, such a product has defects in that gelatin capsules are difficult to administer to animals. Further, the composition only appears to attempt to serve as a protective skin barrier, a temporary treatment. It will not prevent further loss of necessary products to alleviate skin conditions.
Thus while there are some products on the market that utilize ceramides in topical and oral applications for dermal use, improvements can be made on the concept. A food composition for animals that (1) contains active ingredients, (2) improves the symptoms of atopic dermatitis for animal, (3) assists in future care of animal skin and (4) can be given as a treat is desirable.